Rationale: Weight gain in middle-aged women often is associated with declining estrogen at the onset of menopause. Hormone replacement therapy (HRT) can curb postmenopausal weight gain but can also increase the risk of stroke and breast cancer. Understanding how estrogen-responsive neurons regulate physical activity and energy expenditure may lead to the development of novel strategies for treating obesity in women. Approach: We have developed a mouse model of female obesity in which the transcription factor Nkx2-1 is ablated in the ventromedial hypothalamus (VMH) using Sf1-driven CRE recombinase, Nkx2- 1Sf1Cre mice. Female but not male Nkx2-1Sf1Cre mice are obese and exhibit reduced physical activity and fewer ER-positive neurons in the VMH. I hypothesize that estrogen-responsive Nkx2-1 neurons in the VMH regulate physical activity in female mice and that loss of these neurons underlies the couch-potato phenotype observed in Nkx2-1Sf1Cre females. In two aims, I will define how estrogen-responsive Nkx2-1 neurons in the VMH regulate physical activity and determine if they are sufficient to rescue sedentary behavior when transplanted into obese mice. Impact: Nkx2-1Sf1Cre mice offer a unique opportunity to define a sexually dimorphic neuroendocrine center that regulates physical activity. The proposed studies should provide new potential strategies for decreasing sedentary behavior and improving metabolic health in women. Environment: The research mentor is Dr. Holly Ingraham, a leader in the field of developmental neuroendocrinology. Drs. John Rubenstein, Allison Xu, and Allan Basbaum have agreed to serve on an Advisory Committee to provide specialized scientific expertise and guidance in career development. In addition to research training, I propose didactic coursework in neuroscience and the responsible conduct of research. Career goals: I will participate in career development workshops at UCSF to prepare for a career in academic research. Overall, the proposed research and career development training activities will prepare me to become an independent investigator in the field of obesity research.